Nearly 33 million people are infected with HIV worldwide [1,2], and despite extensive efforts, there are no effective vaccines or other countermeasures to protect against HIV transmission [3]. Previous attempts to find effective anti-HIV agents have determined that certain synthetic θ-defensins called “retrocyclins” or “retrocyclin polypeptides” are potent inhibitors of HIV-1 infection [4-8]. Retrocyclins belong to a large family of antimicrobial peptides known as defensins, all of which are cationic, tri-disulfide bonded peptides that have important roles in innate host defense. Based on the position of the cysteines and the disulfide bonding pattern, defensins are grouped into 3 subfamilies: α-defensins, β-defensins and θ-defensins [9, 10].
θ-Defensins such as retrocyclin have a cyclic peptide backbone, derived from the head-to-tail-ligation of two nonapeptides that each contributes nine amino acids to form the 18 residue mature polypeptide [11]. θ-Defensins are the only known cyclic peptides in mammals and were originally isolated from rhesus macaque leukocytes and bone marrow [11-13]. While θ-defensin peptides, e.g., retrocyclin polypeptides, are produced in old world monkeys and orangutans, in humans they exist only as expressed pseudogenes [14]. Critically, a premature termination codon in the signal peptide portion of human retrocyclin mRNA prevents its translation. The retrocyclin gene is otherwise remarkably intact, showing 89.4% identity with rhesus θ-defensins. Its genetic information was utilized to recreate retrocyclins synthetically and confirm their activity against both X4 and R5 strains of HIV-1 [4-7]. To date, however, there has not yet been developed an agent or process for restoring the mammalian body's ability to endogenously produce retrocyclin peptides.